by 22% and blood auc by 15%, without any significant change in metformin renal clearance. when administered with metformin, the cmax and auc of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. no information is available about the interaction of metformin and furosemide when coadministered chronically. nifedipine - a single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin cmax and auc by 20% and 9%, respectively, and increased the amount excreted in the urine. tmax and half-life were unaffected. nifedipine appears to enhance the absorption of metformin. metformin had minimal effects on nifedipine. cationic drugs - cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin auc. there was no change in elimination half-life in the single-dose study. metformin had no effect on cimetidine pharmacokinetics. although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride extended release tablets usp and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. other - certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. these drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. when such drugs are administered to a patient receiving metformin hydrochloride extended release tablets usp, the patient should be closely observed for loss of blood glucose control. when such drugs are withdrawn from a patient receiving metformin hydrochloride extended release tablets usp, the patient should be observed closely for hypoglycemia. in healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

to the maximum dose (see warnings and dosage and administration ). before initiation of metformin hydrochloride extended release tablets usp tablets therapy and at least annually thereafter, renal function should be assessed and verified as normal. in patients in whom development of renal dysfunction is anticipated, renal function should be assessed more frequently and metformin hydrochloride extended release tablets usp discontinued if evidence of renal impairment is present. use of concomitant medications that may affect renal function or metformin disposition - concomitant medication(s) that may affect renal function or result in significant hemodynamic change or may interfere with the disposition of metformin, such as cationic drugs that are eliminated by renal tubular secretion (see precautions: drug interactions ), should be used with caution. radiologic studies involving the use of intravascular iodinated contrast materials (for example, intravenous urogram, intravenous cholangiography, angiography, and computed tomography (ct) scans with intravascular contrast materials) - intravascular contrast studies with iodinated materials can lead to acute alteration of renal function and have been associated with lactic acidosis in patients receiving metformin (see contraindications ). therefore, in patients in whom any such study is planned, metformin hydrochloride extended release tablets usp should be temporarily discontinued at the time of or prior to the procedure, and withheld for 48 hours subsequent to the procedure and reinstituted only after renal function has been re-evaluated and found to be normal. hypoxic states - cardiovascular collapse (shock) from whatever cause, acute congestive heart failure, acute myocardial infarction and other conditions characterized by hypoxemia have been associated with lactic acidosis and may also cause prerenal azotemia. when such events occur in patients on metformin hydrochloride extended release tablets usp therapy, the drug should be promptly discontinued. surgical procedures - metformin hydrochloride extended release tablets usp therapy should be temporarily suspended for any surgical procedure (except minor procedures not associated with restricted intake of food and fluids) and should not be restarted until the patient's oral intake has resumed and renal function has been evaluated as normal. alcohol intake - alcohol is known to potentiate the effect of metformin on lactate metabolism. patients, therefore, should be warned against excessive alcohol intake, acute or chronic, while receiving metformin hydrochloride extended release tablets usp. impaired hepatic function - since impaired hepatic function has been associated with some cases of lactic acidosis, metformin hydrochloride should generally be avoided in patients with clinical or laboratory evidence of hepatic disease. vitamin b12 levels - in controlled clinical trials of metformin hydrochloride tablets of 29 weeks duration, a decrease to subnormal levels of previously normal serum vitamin b12 levels, without clinical manifestations, was observed in approximately 7% of patients. such decrease, possibly due to interference with b12 absorption from the b12-intrinsic factor complex, is, however, very rarely associated with anemia and appears to be rapidly reversible with discontinuation of metformin hydrochloride tablets or vitamin b12 supplementation. measurement of hematologic parameters on an annual basis is advised in patients on metformin hydrochloride extended release tablets usp and any apparent abnormalities should be appropriately investigated and managed (see precautions: laboratory tests ). certain individuals (those with inadequate vitamin b12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin b12 levels. in these patients, routine serum vitamin b12 measurements at two- to three year intervals may be useful. change in clinical status of patients with previously controlled type 2 diabetes - a patient with type 2 diabetes previously well controlled on metformin hydrochloride extended release tablets usp who develops laboratory abnormalities or clinical illness (especially vague and poorly defined illness) should be evaluated promptly for evidence of ketoacidosis or lactic acidosis. evaluation should include serum electrolytes and ketones, blood glucose and, if indicated, blood ph, lactate, pyruvate, and metformin levels. if acidosis of either form occurs, metformin hydrochloride extended release tablets usp must be stopped immediately and other appropriate corrective measures initiated (see also warnings ). hypoglycemia - hypoglycemia does not occur in patients receiving metformin hydrochloride extended release tablets usp alone under usual circumstances of use, but could occur when caloric intake is deficient, when strenuous exercise is not compensated by caloric supplementation, or during concomitant use with other glucose-lowering agents (such as sulfonylureas and insulin) or ethanol. elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency or alcohol intoxication are particularly susceptible to hypoglycemic effects. hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs. loss of control of blood glucose - when a patient stabilized on any diabetic regimen is exposed to stress such as fever, trauma, infection, or surgery, a temporary loss of glycemic control may occur. at such times, it may be necessary to withhold metformin hydrochloride extended release tablets usp and temporarily administer insulin. metformin hydrochloride extended release tablets usp may be reinstituted after the acute episode is resolved. the effectiveness of oral antidiabetic drugs in lowering blood glucose to a targeted level decreases in many patients over a period of time. this phenomenon, which may be due to progression of the underlying disease or to diminished responsiveness to the drug, is known as secondary failure, to distinguish it from primary failure in which the drug is ineffective during initial therapy. should secondary failure occur with either metformin hydrochloride extended release tablets usp or sulfonylurea monotherapy, combined therapy with metformin hydrochloride extended release tablets usp and sulfonylurea may result in a response. should secondary failure occur with combined metformin hydrochloride extended release tablets usp /sulfonylurea therapy, it may be necessary to consider therapeutic alternatives including initiation of insulin therapy.

han placebo-treated patients. diarrhea led to discontinuation of study medication in 0.6% of patients treated with metformin hydrochloride extended release tablets usp. additionally, the following adverse reactions were reported in ≥1.0% - ≤5.0% of metformin hydrochloride extended release tablets usp patients and were more commonly reported with metformin hydrochloride extended release tablets usp than placebo: abdominal pain, constipation, distention abdomen, dyspepsia/heartburn, flatulence, dizziness, headache, upper respiratory infection, taste disturbance.

by 22% and blood auc by 15%, without any significant change in metformin renal clearance. when administered with metformin, the cmax and auc of furosemide were 31% and 12% smaller, respectively, than when administered alone, and the terminal half-life was decreased by 32%, without any significant change in furosemide renal clearance. no information is available about the interaction of metformin and furosemide when coadministered chronically. nifedipine - a single-dose, metformin-nifedipine drug interaction study in normal healthy volunteers demonstrated that coadministration of nifedipine increased plasma metformin cmax and auc by 20% and 9%, respectively, and increased the amount excreted in the urine. tmax and half-life were unaffected. nifedipine appears to enhance the absorption of metformin. metformin had minimal effects on nifedipine. cationic drugs - cationic drugs (e.g., amiloride, digoxin, morphine, procainamide, quinidine, quinine, ranitidine, triamterene, trimethoprim, or vancomycin) that are eliminated by renal tubular secretion theoretically have the potential for interaction with metformin by competing for common renal tubular transport systems. such interaction between metformin and oral cimetidine has been observed in normal healthy volunteers in both single- and multiple-dose, metformin-cimetidine drug interaction studies, with a 60% increase in peak metformin plasma and whole blood concentrations and a 40% increase in plasma and whole blood metformin auc. there was no change in elimination half-life in the single-dose study. metformin had no effect on cimetidine pharmacokinetics. although such interactions remain theoretical (except for cimetidine), careful patient monitoring and dose adjustment of metformin hydrochloride extended release tablets usp and/or the interfering drug is recommended in patients who are taking cationic medications that are excreted via the proximal renal tubular secretory system. other - certain drugs tend to produce hyperglycemia and may lead to loss of glycemic control. these drugs include the thiazides and other diuretics, corticosteroids, phenothiazines, thyroid products, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics, calcium channel blocking drugs, and isoniazid. when such drugs are administered to a patient receiving metformin hydrochloride extended release tablets usp, the patient should be closely observed for loss of blood glucose control. when such drugs are withdrawn from a patient receiving metformin hydrochloride extended release tablets usp, the patient should be observed closely for hypoglycemia. in healthy volunteers, the pharmacokinetics of metformin and propranolol, and metformin and ibuprofen were not affected when coadministered in single-dose interaction studies. metformin is negligibly bound to plasma proteins and is, therefore, less likely to interact with highly protein-bound drugs such as salicylates, sulfonamides, chloramphenicol, and probenecid, as compared to the sulfonylureas, which are extensively bound to serum proteins.

daily. after repeated administration of metformin hydrochloride extended release tablets usp, metformin did not accumulate in plasma. within-subject variability in cmax and auc of metformin from metformin hydrochloride extended release tablets usp is comparable to that with metformin hydrochloride tablets. although the extent of metformin absorption (as measured by auc) from the metformin hydrochloride extended release tablet usp increased by approximately 50% when given with food, there was no effect of food on cmax and tmax of metformin. both high and low fat meals had the same effect on the pharmacokinetics of metformin hydrochloride extended release tablets usp. distribution the apparent volume of distribution (v/f) of metformin following single oral doses of metformin hydrochloride 850 mg tablets averaged 654 ± 358 l. metformin is negligibly bound to plasma proteins, in contrast to sulfonylureas, which are more than 90% protein bound. metformin partitions into erythrocytes, most likely as a function of time. at usual clinical doses and dosing schedules of metformin hydrochloride, steady state plasma concentrations of metformin are reached within 24 to 48 hours and are generally less than 1 μg/ml. during controlled clinical trials of metformin hydrochloride tablets, maximum metformin plasma levels did not exceed 5 μg/ml, even at maximum doses. metabolism and elimination intravenous single-dose studies in normal subjects demonstrate that metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no metabolites have been identified in humans) nor biliary excretion. renal clearance (see table 1 ) is approximately 3.5 times greater than creatinine clearance, which indicates that tubular secretion is the major route of metformin elimination. following oral administration, approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, with a plasma elimination half-life of approximately 6.2 hours. in blood, the elimination half-life is approximately 17.6 hours, suggesting that the erythrocyte mass may be a compartment of distribution. special populations patients with type 2 diabetes in the presence of normal renal function, there are no differences between single- or multiple-dose pharmacokinetics of metformin between patients with type 2 diabetes and normal subjects (see table 1 ), nor is there any accumulation of metformin in either group at usual clinical doses. the pharmacokinetics of metformin hydrochloride extended release tablets usp in patients with type 2 diabetes are comparable to those in healthy normal adults. renal insufficiency in patients with decreased renal function (based on measured creatinine clearance), the plasma and blood half-life of metformin is prolonged and the renal clearance is decreased in proportion to the decrease in creatinine clearance (see table 1 ; also see warnings ). hepatic insufficiency no pharmacokinetic studies of metformin have been conducted in patients with hepatic insufficiency. geriatrics limited data from controlled pharmacokinetic studies of metformin hydrochloride in healthy elderly subjects suggest that total plasma clearance of metformin is decreased, the half-life is prolonged, and cmax is increased, compared to healthy young subjects. from these data, it appears that the change in metformin pharmacokinetics with aging is primarily accounted for by a change in renal function (see table 1 ). metformin hydrochloride treatment should not be initiated in patients ≥ 80 years of age unless measurement of creatinine clearance demonstrates that renal function is not reduced (see warnings and dosage and administration ). table 1: select mean (±s.d.) metformin pharmacokinetic parameters following single or multiple oral doses of metformin hydrochloride. subject groups: metformin hydrochloride dosea (number of subjects) cmaxb (μg/ml) tmaxc (hrs) renal clearance (ml/min) healthy, nondiabetic adults: 500 mg single dose (24) 850 mg single dose (74)d 850 mg three times daily for 19 dosese (9) 1.03 (±0.33) 1.60 (±0.38) 2.01 (±0.42) 2.75 (±0.81) 2.64 (±0.82) 1.79 (±0.94) 600 (±132) 552 (±139) 642 (±173) adults with type 2 diabetes: 850 mg single dose (23) 850 mg three times daily for 19 dosese (9) 1.48 (±0.5) 1.90 (±0.62) 3.32 (±1.08) 2.01 (±1.22) 491 (±138) 550 (±160) elderlyf, healthy nondiabetic adults: 850 mg single dose (12) 2.45 (±0.70) 2.71 (±1.05) 412 (±98) renal-impaired adults: 850 mg single dose mild (clcrg 61-90 ml/min) (5) moderate (clcr 31-60 ml/min) (4) severe (clcr 10-30 ml/min) (6) 1.86 (±0.52) 4.12 (±1.83) 3.93 (±0.92) 3.20 (±0.45) 3.75 (±0.50) 4.01 (±1.10) 384 (±122) 108 (±57) 130 (±90) aall doses given fasting except the first 18 doses of the multiple dose studies bpeak plasma concentration ctime to peak plasma concentration dcombined results (average means) of five studies: mean age 32 years (range 23-59 years) ekinetic study done following dose 19, given fasting felderly subjects, mean age 71 years (range 65-81 years) gclcr = creatinine clearance normalized to body surface area of 1.73 m2 pediatrics after administration of a single oral metformin hydrochloride 500 mg tablet with food, geometric mean metformin cmax and auc differed less than 5% between pediatric type 2 diabetic patients (12 to 16 years of age) and gender- and weight-matched healthy adults (20 to 45 years of age), all with normal renal function. gender metformin pharmacokinetic parameters did not differ significantly between normal subjects and patients with type 2 diabetes when analyzed according to gender (males = 19, females = 16). similarly, in controlled clinical studies in patients with type 2 diabetes, the antihyperglycemic effect of metformin hydrochloride tablets was comparable in males and females. race no studies of metformin pharmacokinetic parameters according to race have been performed. in controlled clinical studies of metformin hydrochloride tablets in patients with type 2 diabetes, the antihyperglycemic effect was comparable in whites (n=249), blacks (n=51), and hispanics (n=24).

e or female rats was unaffected by metformin when administered at doses as high as 600 mg/kg/day, which is approximately three times the maximum recommended human daily dose based on body surface area comparisons.

was increased to 1500 mg once daily if hba1c was ≥7.0% but <8.0% (patients with hba1c ≥8.0% were discontinued from the study). at the final visit (24-week), mean hba1c had increased 0.2% from baseline in placebo patients and decreased 0.6% with metformin hydrochloride extended release tablets usp. a 16-week, double-blind, placebo-controlled, dose-response study of metformin hydrochloride extended release tablets usp, taken once daily with the evening meal or twice daily with meals, was conducted in patients with type 2 diabetes who had failed to achieve glycemic control with diet and exercise (hba1c 7.0%-11.0%, fpg 126-280 mg/dl). changes in glycemic control and body weight are shown in table 6. table 6: summary of mean changes from baseline* in hba1c, fasting plasma glucose, and body weight at final visit (16-week study) metformin hydrochloride extended release tablets usp 500 mg once daily 1000 mg once daily 1500 mg once daily 2000 mg once daily 1000 mg twice daily placebo hemoglobin a1c (%) baseline change at final visit p-valuea (n=115) 8.2 -0.4 <0.001 (n=115) 8.4 -0.6 <0.001 (n=111) 8.3 -0.9 <0.001 (n=125) 8.4 -0.8 <0.001 (n=112) 8.4 -1.1 <0.001 (n=111) 8.4 0.1 - fpg (mg/dl) baseline change at final visit p-valuea (n=126) 182.7 -15.2 <0.001 (n=118) 183.7 -19.3 <0.001 (n=120) 178.9 -28.5 <0.001 (n=132) 181.0 -29.9 <0.001 (n=122) 181.6 -33.6 <0.001 (n=113) 179.6 7.6 - body weight(lbs) baseline change at final visit p-valuea (n=125) 192.9 -1.3 ns** (n=119) 191.8 -1.3 ns** (n=117) 188.3 -0.7 ns** (n=131) 195.4 -1.5 ns** (n=119) 192.5 -2.2 ns** (n=113) 194.3 -1.8 - * all patients on diet therapy at baseline aall comparisons versus placebo ** not statistically significant compared with placebo, improvement in glycemic control was seen at all dose levels of metformin hydrochloride extended release tablets usp and treatment was not associated with any significant change in weight (see dosage and administration for dosing recommendations for metformin hydrochloride extended release tablets usp). a 24-week, double-blind, randomized study of metformin hydrochloride extended release tablets usp, taken once daily with the evening meal, and metformin hydrochloride tablets, taken twice daily (with breakfast and evening meal), was conducted in patients with type 2 diabetes who had been treated with metformin hydrochloride tablets 500 mg twice daily for at least 8 weeks prior to study entry. the metformin hydrochloride tablets dose had not necessarily been titrated to achieve a specific level of glycemic control prior to study entry. patients qualified for the study if hba1c was ≤8.5% and fpg was ≤200 mg/dl. changes in glycemic control and body weight are shown in table 7. table 7: summary of mean changes from baseline* in hba1c, fasting plasma glucose, and body weight at week 12 and at final visit (24-week study) metformin hydrochloride tablets metformin hydrochloride extended release tablets usp 500 mg twice daily 1000 mg once daily 1500 mg once daily hemoglobin a1c (%) baseline change at 12 weeks (95% ci) change at final visit (95% ci) (n=67) 7.06 0.14 (-0.03, 0.31) 0.14a (-0.04, 0.31) (n=72) 6.99 0.23 (0.10, 0.36) 0.27 (0.11, 0.43) (n=66) 7.02 0.04 (-0.08, 0.15) 0.13 (-0.02, 0.28) fpg (mg/dl) baseline change at 12 weeks (95% ci) change at final visit (95% ci) (n=69) 127.2 12.9 (6.5, 19.4) 14.0 (7.0, 21.0) (n=72) 131.0 9.5 (4.4, 14.6) 11.5 (4.4, 18.6) (n=70) 131.4 3.7 (-0.4, 7.8) 7.6 (1.0, 14.2) body weight(lbs) baseline change at 12 weeks (95% ci) change at final visit (95% ci) (n=71) 210.3 0.4 (-0.4, 1.5) 0.9 (-0.4, 2.2) (n=74) 202.8 0.9 (0.0, 2.0) 1.1 (-0.2, 2.4) (n=71) 192.7 0.7 (-0.4, 1.8) 0.9 (-0.4, 2.0) * all patients on metformin hydrochloride tablets 500 mg twice daily at baseline a n=68 after 12 weeks of treatment, there was an increase in mean hba1c in all groups; in the metformin hydrochloride extended release tablets usp 1000 mg group, the increase from baseline of 0.23% was statistically significant (see dosage and administration ). changes in lipid parameters in the previously described placebo-controlled dose-response study of metformin hydrochloride extended release tablets usp are shown in table 8. table 8: summary of mean percent changes from baseline* in major lipid variables at final visit (16-week study) metformin hydrochloride extended release tablets usp 500 mg once daily 1000 mg once daily 1500 mg once daily 2000 mg once daily 1000 mg twice daily placebo total cholesterol (mg/dl) baseline mean % change at final visit (n=120) 210.3 1.0% (n=113) 218.1 1.7% (n=110) 214.6 0.7% (n=126) 204.4 -1.6% (n=117) 208.2 -2.6% (n=110) 208.6 2.6% total triglycerides (mg/dl) baseline mean % change at final visit (n=120) 220.2 14.5% (n=113) 211.9 9.4% (n=110) 198.0 15.1% (n=126) 194.2 14.9% (n=117) 179.0 9.4% (n=110) 211.7 10.9% ldl-cholesterol (mg/dl) baseline mean % change at final visit (n=119) 131.0 -1.4% (n=113) 134.9 -1.6% (n=109) 135.8 -3.5% (n=126) 125.8 -3.3% (n=117) 131.4 -5.5% (n=107) 131.9 3.2% hdl-cholesterol (mg/dl) baseline mean % change at final visit (n=120) 40.8 6.2% (n=108) 41.6 8.6% (n=108) 40.6 5.5% (n=125) 40.2 6.1% (n=117) 42.4 7.1% (n=108) 39.4 5.8% *all patients on diet therapy at baseline changes in lipid parameters in the previously described study of metformin hydrochloride tablets and metformin hydrochloride extended release tablets usp are shown in table 9. table 9: summary of mean percent changes from baseline* in major lipid variables at final visit (24-week study) metformin hydrochloride tablets metformin hydrochloride extended release tablets usp 500 mg twice daily 1000 mg once daily 1500 mg once daily total cholesterol (mg/dl) baseline mean % change at final visit (n=68) 199.0 0.1% (n=70) 201.9 1.3% (n=66) 201.6 0.1% total triglycerides (mg/dl) baseline mean % change at final visit (n=68) 178.0 6.3% (n=70) 169.2 25.3% (n=66) 206.8 33.4% ldl-cholesterol (mg/dl) baseline mean %change at final visit (n=68) 122.1 -1.3% (n=70) 126.2 -3.3% (n=66) 115.7 -3.7% hdl-cholesterol (mg/dl) baseline mean % change at final visit (n=68) 41.9 4.8% (n=70) 41.7 1.0% (n=65) 44.6 -2.1% *all patients on metformin hydrochloride tablet 500 mg twice daily at baseline

estinal symptoms, which are common during initiation of metformin therapy, are unlikely to be drug related. later occurrence of gastrointestinal symptoms could be due to lactic acidosis or other serious disease. patients should be counselled against excessive alcohol intake, either acute or chronic, while receiving metformin hydrochloride extended release tablets usp. metformin hydrochloride extended release tablets usp alone does not usually cause hypoglycemia, although it may occur when metformin hydrochloride extended release tablets usp is used in conjunction with oral sulfonylureas and insulin. when initiating combination therapy, the risks of hypoglycemia, its symptoms and treatment, and conditions that predispose to its development should be explained to patients and responsible family members. (see patient information printed below.) patients should be informed that metformin hydrochloride extended release tablets usp must be swallowed whole and not crushed or chewed, and that the inactive ingredients may occasionally be eliminated in the feces as a soft mass that may resemble the original tablet.